201247637 六、發明說明： I：發明所屬之技術領域】 發明領域 本發明係有關於一種作為抗菌劑、抗真菌劑等有用的 1,2-苯并異噻唑-3-酮化合物之製造方法。 JL ^tr 4^. ϋ 發明背景 1，2-苯并異噻唑-3-酮化合物係作為抗菌劑、抗真菌劑 等有用的化合物，作為其製造方法，在下述專利文獻1，係 記載使2-(烷硫基）苯曱腈類與_化劑在水的存在下進行反 應之方法（專利文獻1)。依照該方法，將2-(烷硫基）苯曱腈化 合物與水添加之後，添加鹵化劑而使其反應，雖然產率係 比較高，但是有進一步改善的餘地。 先前技術文獻 專利文獻 [專利文獻1]曰本專利特開平8-134051號公報 【發明内容】 發明概要 發明欲解決之課題 本發明之主要目的，係提供一種以高產率、簡易且經 濟地製造高純度的1，2-苯并異噻唑-3-酮化合物之方法。 用以欲解決課題之手段 為了達成上述目的，本發明者重複專心研究的結果。 其結果，發現在水的存在下使2-(烷硫基）苯曱腈化合物與鹵 201247637 化劑反應而製造1,2-苯并異噻唑-3-酮化合物之方法，藉由 將鹵化劑與水併行而徐緩地添加至含有作為原料的2 -(烷硫 基）苯甲腈化合物之反應系統而使反應進行之方法，能夠抑 制副反應和生成物的水解反應而能夠以高產率製造高純度 的1，2-苯并異噻唑-3-酮化合物，而完成了本發明。 亦即，本發明係提供一種下述之1，2-苯并異噻唑-3-酮 化合物之製造方法。 項1.一種1,2-苯并異噻唑-3-酮化合物之製造方法，其係藉由 使以通式（1): [化1]201247637 VI. Description of the Invention: I: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for producing a 1,2-benzisothiazol-3-one compound useful as an antibacterial agent, an antifungal agent or the like. BACKGROUND OF THE INVENTION 1,2-benzisothiazol-3-one compound is a useful compound such as an antibacterial agent or an antifungal agent, and a method for producing the same is disclosed in Patent Document 1 below. A method in which a (alkylthio)benzonitrile is reacted with a _chemical in the presence of water (Patent Document 1). According to this method, after the 2-(alkylthio)benzonitrile compound is added with water, a halogenating agent is added and reacted, and although the yield is relatively high, there is room for further improvement. CITATION LIST Patent Literature [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei No. 8-134051. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION The main object of the present invention is to provide a high productivity, simple and economical manufacture. A method of purifying a 1,2-benzisothiazol-3-one compound. Means for Solving the Problem In order to achieve the above object, the inventors repeated the results of intensive research. As a result, a method of producing a 1,2-benzisothiazol-3-one compound by reacting a 2-(alkylthio)benzonitrile compound with a halogen 201247637 compound in the presence of water was found, by using a halogenating agent. A method in which a reaction system is carried out by adding a reaction system containing a 2-(alkylthio)benzonitrile compound as a raw material in parallel with water, thereby suppressing a side reaction and a hydrolysis reaction of a product, and can be produced at a high yield. The 1,2-benzisothiazol-3-one compound of purity was completed, and the present invention was completed. That is, the present invention provides a method for producing the following 1,2-benzisothiazol-3-one compound. Item 1. A method for producing a 1,2-benzisothiazol-3-one compound by using the general formula (1): [Chemical Formula 1]
(式中，R1係表示氫原子、碳數1〜4的烷基、碳數1〜4的 烷氧基、硝基、羧基、烷氧基羰基、或鹵素原子，R2係表 示碳數1〜4的烷基）表示之2-(烷硫基）苯曱腈化合物與鹵化 劑在水的存在下反應，而製造以通式(2): [化2] Ο(wherein R1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a carboxyl group, an alkoxycarbonyl group or a halogen atom, and R2 represents a carbon number of 1 to 2). The 2-(alkylthio)benzonitrile compound represented by the alkyl group of 4 is reacted with a halogenating agent in the presence of water to produce the formula (2): [Chemical 2]
(式中，R1係與上述相同）表示之1,2-苯并異噻唑-3-酮化 合物之方法，其特徵在於包含以下步驟：在含有2-(烷硫基) 苯曱腈化合物之反應系統中，將鹵化劑與水併行而一邊徐 201247637 緩地添力σ —、息,i 邊使反應進行之步驟。 .述項1之1,2_苯并異噻唑酮化合物之製造方法， 二目斜於添加至反應系統之函化劑莫耳數，使 1在從0.5供苢甘 、耳不足之量至0.5倍莫耳過剩之量的範圍 :’：一與水併行添加至反應系統。 法1上述項！或2之i，2-笨并異噻唾_3-酮化合物之製造方 法’其中_化劑係氯或硫醯氯(sulfuryl chloride)。 X下，具體地說明本發明之丨,2_苯并異噻唑_3_酮化入 物之製造方法。 σ 原料化合物 (1)在本發明所使用的原料之中，在以通式（1): [化3]A method of a 1,2-benzisothiazol-3-one compound represented by the formula (wherein R1 is the same as defined above), characterized by comprising the step of: reacting a compound containing 2-(alkylthio)benzonitrile In the system, the halogenating agent is added to the water in parallel with the step 201247637, and the reaction is carried out while the reaction is carried out. The method for producing a 1,2-benzisothiazolone compound according to Item 1, wherein the dichroic is added to the molar number of the functionalizing agent added to the reaction system, so that 1 is from 0.5 to 5%, and the amount is less than 0.5. The range of the amount of excess of Momo: ': One is added to the reaction system in parallel with water. Law 1 above! Or a method for producing i,2-stupothi-iso-salt-3-one compound, wherein the chemical is chlorine or sulfuryl chloride. In the case of X, a method for producing a 2_benzisothiazol-3-yl ketone can be specifically described. σ Raw material compound (1) Among the raw materials used in the present invention, the general formula (1): [Chemical 3]
(式中’ R1係表示氫原子、碳數丨〜4的烷基、碳數丨〜4的 烷氧基、硝基、羧基、烷氧基羰基、或鹵素原子，R2係表 不石反數1〜4的烷基)表示之2-(烷硫基）苯甲腈化合物，以R1表 示的基之中，作為碳數1〜4的烷基，可例示甲基、乙基、正 丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基等 的直鏈狀或分枝鏈狀之碳數1〜4的烷基。作為碳數1〜4的烷 氧基，例如可舉出甲氧基、乙氧基、正丙氧基、異丙氧基、 正丁氧基、異丁氧基、第二丁氧基、第三丁氧基等。作為 烷氧基羰基’係具有碳數1〜4的直鏈狀或分枝鏈狀的烷基之 201247637 烷氧基羰基，例如可舉出甲氧基羰基、乙氧基羰基、丙氧 基羰基、丁氧基羰基等。作為鹵素原子，可例示氯原子、 溴原子等。 該等以R1表示的基之中，以氫原子、甲基、乙基、第 一 丁基甲氧基、甲氧基Ik基、乙氧基幾基、丙氧基幾基、 氯原子、硝基等為特佳。 以R表示之碳數1〜4的烧基，可例示與以Ri表示的基之 烷基同樣的基，該等之中，以曱基、乙基、正丙基第三 丁基等為佳。 作為以通式（1)表示之2_(院硫基）苯甲腈化合物的具體 例，例如可舉出2-(曱硫基）苯曱腈、2_(乙硫基）苯甲腈、2•(正 丙硫基）苯曱腈、2-(第三丁硫基）苯甲腈、3·甲基_2_(曱硫基） 苯曱腈、5-第三丁基_2-(曱硫基）苯甲腈、4-甲氧基_2_(甲硫 基)苯曱腈、3-硝基-2-(曱硫基)苯曱腈、3_硝基(第三丁硫 基）苯曱腈、4·氣-2-(曱硫基）苯曱腈、4-羧基-2-(甲硫基)苯 曱腈、4甲氧基羰基_2_(曱硫基)苯曱腈。該等之中，從容易 取且生成物的抗菌性優良之觀點，以2_(曱硫基）笨甲腈、3_ 曱基-2-(曱硫基）苯甲腈、5_第三丁基_2_(曱硫基)苯甲腈、 曱氧基-2-(甲硫基)笨曱腈、3-硝基_2-(第三丁硫基）苯甲腈、 4-氣-2-(曱硫基)苯甲腈及4甲氧基羰基_2 (甲硫基）苯甲腈為 佳。 作為以通式（1)表示之2 -(院硫基）苯曱腈化合物，係可以 使用藉由任何方法所製造者。例如專利文獻丨（特開平 8-134051號公報)所記載，能夠使用藉由將以式(3): 201247637 [化4](In the formula, R1 represents a hydrogen atom, an alkyl group having a carbon number of 4~4, an alkoxy group having a carbon number of 丨~4, a nitro group, a carboxyl group, an alkoxycarbonyl group, or a halogen atom, and R2 represents an inverse number of stones. The 2-(alkylthio)benzonitrile compound represented by the alkyl group of 1 to 4, wherein the alkyl group having 1 to 4 carbon atoms is a group represented by R1, and a methyl group, an ethyl group, a n-propyl group can be exemplified. A linear or branched chain alkyl group having 1 to 4 carbon atoms such as isopropyl, n-butyl, isobutyl, t-butyl or t-butyl. Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a second butoxy group. Tributoxy and the like. The 201247637 alkoxycarbonyl group having a linear or branched chain alkyl group having 1 to 4 carbon atoms as an alkoxycarbonyl group may, for example, be a methoxycarbonyl group, an ethoxycarbonyl group or a propoxycarbonyl group. , butoxycarbonyl and the like. The halogen atom may, for example, be a chlorine atom or a bromine atom. Among the groups represented by R1, a hydrogen atom, a methyl group, an ethyl group, a first butyl methoxy group, a methoxy group Ik group, an ethoxy group, a propoxy group, a chlorine atom, a nitro group, etc. It is especially good. The alkyl group having a carbon number of 1 to 4 represented by R may, for example, be the same group as the alkyl group represented by Ri, and among these, a mercapto group, an ethyl group, a n-propyl tert-butyl group or the like is preferable. . Specific examples of the 2-(indolyl)benzonitrile compound represented by the formula (1) include 2-(indolylthio)benzonitrile and 2-(ethylthio)benzonitrile, 2•. (n-propylthio)benzonitrile, 2-(t-butylthio)benzonitrile, 3·methyl_2_(decylthio)benzonitrile, 5-t-butyl-2-(sulfuron) Benzocarbonitrile, 4-methoxy-2-(methylthio)benzonitrile, 3-nitro-2-(decylthio)benzonitrile, 3-nitro(t-butylthio)benzene Nitrile, 4·gas-2-(decylthio)benzonitrile, 4-carboxy-2-(methylthio)benzonitrile, 4-methoxycarbonyl_2_(decylthio)benzonitrile. Among these, from the viewpoint of easy availability and excellent antibacterial property of the product, 2_(indolylthio)benzonitrile, 3-mercapto-2-(indolylthio)benzonitrile, 5_t-butyl group _2_(曱thio)benzonitrile, 曱oxy-2-(methylthio)benzonitrile, 3-nitro-2-(t-butylthio)benzonitrile, 4-gas-2- (曱thio)benzonitrile and 4-methoxycarbonyl 2 (methylthio)benzonitrile are preferred. As the 2-(indolyl)benzonitrile compound represented by the formula (1), those produced by any method can be used. For example, it can be used by using the formula (3): 201247637 [Chemical 4] as described in the Japanese Patent Publication No. Hei 8-134051.
(式中，R1係與在式（1)之R1相同的基，X係氣或溴原子) 表示之2-苯甲腈化合物與以式（4): [化5] R2SH (4) (式中，R2係表示與在式（1)之R2相同的原子或基）表示 之烧硫醇(alkanethiol)，在驗的存在下且不均勻系使其進行 反應所製成者。 在本發明所使用的原料之中，作為鹵化劑，例如能夠 使用氣、溴、硫醯氣(sulfuryl chloride)、硫醯溴等。該等之 中，從經濟性的觀點，以氣、硫醯氣等為佳。 1,2-苯并異噻唑-3-酮化合物之製造方法 本發明的1,2-苯并異噻唑-3-酮化合物之製造方法係藉 由使以通式（1): [化6](wherein R1 is a group similar to R1 in the formula (1), a X-form gas or a bromine atom) is a 2-benzonitrile compound and is represented by the formula (4): [Chemical 5] R2SH (4) In the above, R2 represents an alkanethiol represented by the same atom or group as R2 of the formula (1), and is produced by reacting in the presence of the test and unevenly. Among the raw materials used in the present invention, as the halogenating agent, for example, gas, bromine, sulfuryl chloride, sulfonium bromide or the like can be used. Among these, from the economic point of view, it is preferable to use gas, sulfur, and the like. Process for producing a 1,2-benzisothiazol-3-one compound The method for producing a 1,2-benzisothiazol-3-one compound of the present invention is obtained by the formula (1): [Chem. 6]
(式中，R1係表示氫原子、碳數1〜4的烷基、碳數1〜4的 烷氧基、硝基、羧基、烷氧基羰基、或鹵素原子，R2係表 201247637 示碳數1〜4的烷基）表示之2-(烷硫基）苯曱腈化合物與_化 劑在水的存在下反應而製造以通式(2): [化7] J I^nh (2) 人s (式中’ R1係與上述相同）表示之1,2-苯并異噻唑-3-綱化 合物之方法。 在該方法中，相對於1莫耳2-(烷硫基）苯甲腈化合物， 鹵化劑的使用量係以0.8〜3莫耳左右為佳，以1〜2莫耳左右 為較佳。鹵化劑的使用量太少時，未反應的2-(院硫基)苯甲 腈化合物太多，有產率低落之可能性。又，鹵化劑的使用 量太多時’容易產生副反應，有產率低落之可能性。 水的使用量係相對於1莫耳2-(烷硫基）苯甲腈化合物， 以0_8~3莫耳左右為佳，以1〜2莫耳左右為較佳。水的使用 量在該範圍外時，有產生副反應致使產率低落之可能性， 乃是不佳。 又，水亦可以添加無機酸而作為無機酸水溶液而使 用。作為無機酸，例如能夠使用鹽酸、硫酸、硝酸等。無 機酸水溶液的濃度係沒有特別限定，通常，鹽酸時係1〇重 量°/〇〜飽和濃度，硫酸或硝酸時係適合使用1〇〜50重量％者 藉由在水添加無機酸，反應的選擇性提升而能夠抑制丨產 物的生成。 必要 本發明方法係未必需要使用反應溶劑，但是身安 8 201247637 而能夠使用反應溶劑。藉由使用反應溶劑，多半的情況係 能夠使反應更順利地進行。 作為反應溶劑，只要對反應為惰性的非水溶劑，沒有 特別限定而能夠使用。 作為此種反應溶劑的具體例，可舉出正己烷、環己烷、 正庚烷等的烴類；二氣乙烷、二氣曱烷、氣仿等的ii化烴 類；苯、甲苯、二甲苯、一氯苯等的芳香族烴類；N，N-二 甲基曱醯胺、二甲基亞砜等。該等之中，以甲苯及一氣苯 為佳。 使用反應溶劑時，其使用量係相對於100質量份2-(烷硫 基）苯曱腈化合物，通常係20〜3000質量份左右即可。反應 溶劑的使用量太少時，藉由添加反應溶劑的效果無法充分 地發揮，反應溶劑的使用量太多時，容積效率有變差之可 能性。 以通式（1)表示之2-(烷硫基）苯曱腈化合物、鹵化劑及水 之反應係通常能夠在-20〜170°C左右，較佳是20〜100°C左右 進行。反應溫度太低時，因為反應速度慢而反應需要長時 間，乃是不佳。另一方面，反應溫度太高時，因為容易產 生副反應，乃是不佳。 反應時間係因反應溫度等而異，通常為0.5〜40小時左 右。 本發明係在藉由上述條件使以通式（1)表示之2-(烷硫 基）苯甲腈化合物與鹵化劑反應時，在含有2-(烷硫基）苯曱 腈化合物之反應系統中，將鹵化劑與水併行而一邊徐緩地 201247637 添加—邊使反應進行係必要的。 使反1°此，藉㈣純劑與水併行而-邊徐緩地添加-邊 使反應進行，㈣抑 透 绅产日上 〗夂應和生成物的水解反應而以高 、.屯度且向收率得到以通式（2): [化8](wherein R1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitro group, a carboxyl group, an alkoxycarbonyl group, or a halogen atom; and R2 is a carbon number of 201247637; A 2-(alkylthio)benzonitrile compound represented by an alkyl group of 1 to 4 is reacted with a _chemical agent in the presence of water to produce a formula (2): [Chemical 7] JI^nh (2) The method of s (wherein R1 is the same as above) represents a 1,2-benzisothiazol-3-yl compound. In this method, the halogenating agent is preferably used in an amount of about 0.8 to 3 moles, preferably about 1 to 2 moles, per mole of the 2-mole 2-(alkylthio)benzonitrile compound. When the amount of the halogenating agent used is too small, the unreacted 2-(indolylthio)benzonitrile compound is too much, and there is a possibility that the yield is low. Further, when the amount of the halogenating agent used is too large, a side reaction tends to occur, and there is a possibility that the yield is lowered. The amount of water used is preferably from about 0 to about 8 moles, preferably from about 1 to about 2 moles, per mole of the 2-mole 2-(alkylthio)benzonitrile compound. When the amount of water used outside this range, there is a possibility that a side reaction causes a decrease in productivity, which is not preferable. Further, water may be added as a mineral acid aqueous solution by adding a mineral acid. As the inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid or the like can be used. The concentration of the aqueous solution of the inorganic acid is not particularly limited. Usually, hydrochloric acid is used in an amount of 1 〇 to 饱和 to a saturated concentration, and in the case of sulfuric acid or nitric acid, it is preferably used in an amount of 1 〇 to 50% by weight. The increase in sex can suppress the formation of hydrazine products. It is not necessary to use the reaction solvent in the method of the present invention, but the reaction solvent can be used as in the case of 2012 Pat. By using a reaction solvent, most of the cases enable the reaction to proceed more smoothly. The reaction solvent is not particularly limited and can be used as long as it is inert to the reaction. Specific examples of such a reaction solvent include hydrocarbons such as n-hexane, cyclohexane, and n-heptane; ii-hydrocarbons such as di-hexane, dioxane, and gas; benzene and toluene; An aromatic hydrocarbon such as xylene or monochlorobenzene; N,N-dimethylguanamine or dimethyl sulfoxide. Among these, toluene and monogas are preferred. When the reaction solvent is used, the amount thereof is usually from about 20 to 3,000 parts by mass based on 100 parts by mass of the 2-(alkylthio)benzonitrile compound. When the amount of the reaction solvent used is too small, the effect of adding the reaction solvent cannot be sufficiently exhibited, and when the amount of the reaction solvent used is too large, the volumetric efficiency may be deteriorated. The reaction system of the 2-(alkylthio)benzonitrile compound represented by the formula (1), a halogenating agent and water can be usually carried out at about -20 to 170 ° C, preferably about 20 to 100 ° C. When the reaction temperature is too low, it is not preferable because the reaction rate is slow and the reaction takes a long time. On the other hand, when the reaction temperature is too high, it is not preferable because a side reaction is liable to occur. The reaction time varies depending on the reaction temperature and the like, and is usually about 0.5 to 40 hours. The present invention is a reaction system containing a 2-(alkylthio)benzoquinone compound when the 2-(alkylthio)benzonitrile compound represented by the formula (1) is reacted with a halogenating agent by the above conditions. In the case where the halogenating agent is added in parallel with water and slowly added to 201247637, it is necessary to carry out the reaction. Let the reverse 1°, by (4) the pure agent and the water in parallel - while slowly adding - while the reaction proceeds, (4) inhibiting the production of the 夂 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和 和The yield is obtained by the general formula (2): [Chemical 8]
(2) 合物 (式中，R1係與上述相同）表示之u_苯并異嘆唾_3· 化 針對自化顯水的添加方法係沒有特·定為 制田彳反應和水解反應而將產率 ’、“ ^ ^約㈣莫耳數时切兩者併行而添加為佳。 常系相對於添加至反應系統中之齒 使水的添加量在歡5倍莫耳r之量至Q5倍莫耳過^ 量的範圍内為佳’以從〇.2倍莫耳不足之量至〇2倍莫耳過剩 之量的為較佳，以從〇」倍莫耳不足之量至Μ倍莫耳 過剩之量的範圍内為更佳。 因為相對於函化劑的添加量，水的添加量太少時，容 易產生副反應’另一方面’相對於画化劑的添加量，水的 添加量太多時，會促進生成物的分解反應，任一者的情況 均是產率低落，乃是不佳。 針對添加函化劑與水之速度，因為係按照反應溫度等 201247637 而異’不可一概地規定，基於具體的反應溫度，在反應所 需要的時間内適當地分配而連續或間歇地添加即可。 例如將總反應時間的i/ΙΟ以上、較佳是總反應時間的 1/2以上設作化劑與水的添加時間’在該時間内，將鹵化 劑與水盡可能均等且間歇或連續地添加即可。因而，可以 在總反應時間範圍將齒化劑與水併行而徐緩地添加至反應 系統’或者亦可將_化劑與水併行而徐緩地添加至反應系 統之後，進一步在上述的反應溫度區域，較佳是在比添加 齒化劑與水時的溫度更高之溫度範圍繼續加熱。又，亦可 以疋在上述之水的添加範圍内在反應系統中預先含有一 部分的水。此時，亦可在反應系統含有之水的量，係 相對於2-(烷硫基）苯甲腈化合物丨莫耳，可以是丨莫耳左右以 下’以0.5莫耳左右以下為佳，以Q2莫耳左^以下為較佳。 依照上述的方法，按照具體的反應條件和添加條件， 例如忐夠以9 9 %以上的高產率得到純度高於9 9 %左右之高 純度的目標物。 如此進行而得到的丨，2-苯并異噻唑-3-酮化合物，係例 如藉由使其從含有該化合物之反躲直接結晶析出、或萃 取而使其再結晶之方法等，能夠容易地離析純化。 作為如此進行而得到的目標化合物亦即以通式(2)表示 之1，2-苯并異噻唑_3_酮化合物的具體例，例如可舉出H 苯并異7·甲基]，2_苯并異嗟。坐_3·酮、5_第三丁 基-1’2-笨并異噻唑_3_酮、6•曱氧基_丨，2_苯并異噻唑-酮、 7_破基'1,2_苯并異。塞唾·3·_、6-氯-1，2-苯并異嗔嗤_3_酮、 201247637 6-敌基-1，2-笨并異嗔唾_3-酮及6-甲氧基幾基-1,2-苯并異》塞 唑-3-酮等。 發明效果 依照本發明，能夠以高純度的化合物之方式，高產率、 簡易且經濟地製造作為抗菌劑、抗真菌劑等有用之1，2-苯并 異°塞。坐-3-酮化合物。 I：實施方式3 用以實施發明之形態 以下’藉由製造例、實施例及比較例，更詳細地說明 本發明，但是本發明不只有限定於該等實施例。 製造例1(2-(甲硫基)苯甲腈的合成） 在具備攪拌機、溫度計、滴液漏斗及冷卻管之内容積 為500mL的四口燒瓶，在氮氣環境下添加27.5g(0.2莫耳)之 2-氣本甲腈、3〇.〇g—氣苯及l.Og之50重量％漠化四正丁铵水 溶液，邊攪拌邊於60〜65〇C以5小時滴入5Mg(0_22莫耳）之 30重量。/〇甲硫醇的鈉鹽水溶液’滴入結束後，進而於同溫 度使其反應12小時。 反應結束後，藉由將反應液冷卻至室溫且將溶劑館去 之後，進行減壓蒸餾，得到29.5g(沸點139〜140°C/931Pa)之 2-(甲硫基)苯甲腈。相對於2-氣苯甲腈之產率為98〇/〇。 實施例1 在具備攪拌機、溫度計及冷卻管之内容積為5〇〇m L的 四口燒瓶，添加在製造例1所得到之29.8g(02莫耳）2_(曱硫 基）苯甲腈、50.0g —氣苯及0_7g(〇.〇4莫耳）水，邊攪拌邊於 12 201247637 45〜50t；以2小時吹入15補·22莫耳）氣，同時將3離2莫 耳）水㈣地以2小時滴人。吹人氣及水的滴入結束後，進 而於65〜70°C加熱而使其反應1小時。 反應結束後，於同溫度添加41 〇g之2〇重量％氫氧化 水溶液且冷卻至室溫。將所析出的結晶過滤分開使用一 氣苯洗淨且乾燥而得到29.9g(0.l98莫耳苯并異噻唑 冬酮。相對於2-(甲硫基）苯甲腈之產率為齊。。所得到的α 苯并異噻唑-3-酮之純度，使用高速液體層析法測定之結 果，為99.8%。 實施例2 在具備攪拌機、溫度計' 滴液漏斗及冷卻管之内容積 為500mL的四口燒瓶，在氮氣環境下添加27 5g(〇 2莫耳)2_ 氣苯曱腈、30g —氣苯及lg之50重量％溴化四正丁銨水溶 液’邊稅拌邊於60~65C以5小時滴入5i.4g(〇.22莫耳)之3〇 重量％曱硫醇的鈉鹽水溶液，滴入結束後，進而於同溫度 使其反應12小時。藉由該操作而得到2_(甲硫基)苯甲腈。 反應結束後，將反應液冷卻至室溫，分液而得到有機 層之後，在所得到之有機層添加〇.7g(〇 〇4莫耳)水，邊攪拌 邊於45〜5〇°C以2小時吹入15.6g(0.22莫耳）氣，同時將 3.6g(0.2莫耳)水同樣地，以2小時滴入。吹入氣及水的滴入 結束後，進而於65〜70。(：加熱而使其反應1小時。 反應結束後，於同溫度添加41.〇g之2〇重量％氫氧化鈉 水溶液且冷卻至室溫。將所析出的結晶過濾分開，使用一 氣苯洗淨且乾燥而得到29.9g(0.198莫耳）之1,2-笨并異噻唑 13 201247637 -3-酮。相對於2_氣苯曱腈之產率為99Q/(^所得到的I，。苯并 異噻唑-3-酮之純度，使用高速液體層析法測定之結果，為 99.8%。 。 ‘ 實施例3 在實施例1，除了使用35.4g(〇.2莫耳）之3_甲基_2_(乙硫 基)苯曱腈代替29.8g(0_2莫耳）2-(曱硫基)苯甲腈以外，與實 施例1同樣地進行而得到31 7g(0 192莫耳）之7_甲基苯 并異噻唑-3-酮化合物，相對於3_甲基(乙硫基）笨曱腈化 合物之產率為96%。所得到的7_甲基_丨，2_笨并異噻唑酮 之純度，使用高速液體層析法測定之結果，為99 6%。 實施例4 在具備攪拌機、溫度計及冷卻管之内容積為5〇〇m L的 四口燒瓶，添加41.〇g(〇.2莫耳）之5-第三丁基_2_(甲硫基）苯 曱腈、50,〇g一氣苯及〇7g(〇〇4莫耳)水，邊攪拌邊於45〜5〇 C將29.7g(〇.22莫耳)硫醯氣及3.6g(0.2莫耳）水雙方同時以2 小時滴入。滴入結束後’進而於65〜7〇t加熱而使其反應1 小時。 反應結束後，於同溫度添加41.〇g之20重量％氫氧化鈉 水溶液且冷卻至室溫。將所析出的結晶過濾分開，使用一 氯苯洗淨且乾燥而得到4〇.2g(〇.194莫耳）之5-第三丁基-1，2-苯并異噻唑-3-酮。相對於5-第三丁基-2-(甲硫基）苯甲腈之 產率為97%。所得到的5-第三丁基_丨，2_苯并異噻唑_3•酮之 純度’使用高速液體層析法測定之結果，為99 5〇/〇。 實施例5 201247637 在具備授拌機、溫度計及冷卻管之内容積為5〇〇m [的 四口燒瓶，添加36.7g(0.2莫耳)之4'氛·2_(曱硫基）苯甲猜、 5〇.〇g-氯苯及l.lg(水0.04莫耳)之35重量％鹽酸，邊攒拌邊 ;45 50 C將l5.6g(〇.22莫耳）氯以2小時吹入、邊同時將 5.5g(水〇·2莫耳)之35重量％的鹽酸同樣地以2小時滴入。氣 的吹入及水的滴人結束後，進而祕〜贼加熱錢其反應 1小時。 反應結束後，於同溫度添加4丨0g之20重量％氫氧化鈉 水溶液且冷卻至室溫。將所析出的結晶過渡分開，使用一 氯苯洗淨且乾燥而得到36.0g(0194莫耳）之卜氣-丨^-苯并異 嘆。坐-3-嗣。相對於4_氯_2_(甲硫基)苯甲腈之產率為97%。所 得到的6·氣-1，2-苯并異嗔唾_3__之純度，使用高速液體層 析法測定之結果，為99.70/〇。 比較例1 在具備攪拌機、溫度計及冷卻管之内容積為5〇〇m [的 四口燒瓶，添加29.8g(0.2莫耳）之2-(甲硫基）苯甲腈、5〇〇g ~氣苯及4.3g(0.24莫耳）水，邊攪拌邊於45〜5〇它將 I5.6g(0_22莫耳）氣以2小時吹入’進而於65〜心加熱而使 其反應1小時。 反應結束後，於同溫度添加4i.〇g之2〇重量％氫氧化鈉 水溶液且冷卻至室溫。將所析出的結晶過濾分開，使用一 氣苯洗淨且乾燥而得到29.0g(0.192莫耳）之1，2_笨并異噻坐 -3-酮。相對於2-(曱硫基）苯曱腈之產率為96%。所得到的夏孓 笨并異噻唑-3-酮之純度，使用高速液體層析法測定之結 15 201247637 果，為97.1%。 C圖式簡單說明3 (無） 【主要元件符號說明】 (無） 16(2) The compound (wherein R1 is the same as the above) represents the addition method of u_benzoxanthene _3··············································· It is better to add the two in parallel with the yield of ', ^ ^ about (four) moles. Often the amount of water added to the teeth in the reaction system is 5 times the molar amount to Q5. It is better to use the amount of 倍 耳 2 量 量 量 量 量 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 The range of excess amount of mole is better. When the amount of water added is too small with respect to the amount of addition of the functionalizer, it is easy to cause a side reaction 'on the other hand' with respect to the amount of the paint to be added. When the amount of water added is too large, the decomposition of the product is promoted. In the case of either reaction, the yield is low, but it is not good. The rate of addition of the solubilizing agent to water may vary depending on the reaction temperature, etc. 201247637, and may be appropriately or continuously added in a time required for the reaction based on the specific reaction temperature, and may be continuously or intermittently added. For example, i/ΙΟ or more of the total reaction time, preferably 1/2 or more of the total reaction time, is set as the addition time of the agent and water. In this time, the halogenating agent and water are as equal as possible and intermittently or continuously. Add it. Therefore, the toothing agent can be slowly and continuously added to the reaction system in parallel with the water in the total reaction time range. Alternatively, the agent can be added to the reaction system in parallel with water, and further in the above reaction temperature region. It is preferred to continue heating at a temperature range higher than the temperature at which the toothing agent and water are added. Further, it is also possible to preliminarily contain a part of water in the reaction system within the range of addition of the above water. In this case, the amount of water contained in the reaction system may be about 2 mol% or less with respect to the 2-(alkylthio) benzonitrile compound, and may be about 0.5 mol or less. Q2 Moir left ^ is preferred. According to the above method, according to the specific reaction conditions and addition conditions, for example, a high purity product having a purity higher than about 99% can be obtained in a high yield of 99% or more. The oxime, 2-benzisothiazol-3-one compound obtained in this manner can be easily obtained by, for example, directly crystallizing or extracting from the compound containing the compound to recrystallize it. Separation and purification. Specific examples of the 1,2-benzisothiazol-3-enone compound represented by the formula (2), which is obtained as described above, may, for example, be H benzoiso 7 methyl group, 2 _Benzene is different. Sitting _3·ketone, 5_t-butyl-1'2-stupothisothiazole_3-ketone, 6•methoxy-丨, 2_benzisothiazol-one, 7_breaking base 1 2_Benzene is different. Saskatchewan·3·_,6-chloro-1,2-benzisoindole_3_one, 201247637 6-enyl-1,2-stupidinyl s-ketone and 6-methoxy Alkyl-1,2-benzisoxedoxazole-3-one and the like. EFFECTS OF THE INVENTION According to the present invention, a 1,2-benzopyrene which is useful as an antibacterial agent or an antifungal agent can be produced in a high yield, simple and economical manner in the form of a highly pure compound. Take a 3-ketone compound. I. Embodiment 3 Mode for Carrying Out the Invention Hereinafter, the present invention will be described in more detail by way of Production Examples, Examples and Comparative Examples, but the present invention is not limited to the Examples. Production Example 1 (Synthesis of 2-(methylthio)benzonitrile) A four-necked flask having a 500 mL internal volume of a stirrer, a thermometer, a dropping funnel, and a cooling tube was added, and 27.5 g (0.2 mol) was added under a nitrogen atmosphere. 2 - gas carbonitrile, 3 〇. 〇 g - gas benzene and l. Og of 50% by weight of desertified tetra-n-butylammonium aqueous solution, while stirring, at 60~65 〇C, 5M into 5Mg (0_22) Moore) 30 weight. After the completion of the dropwise addition of the sodium salt solution of methyl mercaptan, the reaction was further carried out at the same temperature for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature and the solvent was evaporated, and then distilled under reduced pressure to obtain 29.5 g (yield: 139 to 140 ° C / 931 Pa) of 2-(methylthio)benzonitrile. The yield relative to 2-gasbenzonitrile was 98 Å/〇. Example 1 A four-necked flask equipped with a stirrer, a thermometer, and a cooling tube having an internal volume of 5 μm L was added to 29.8 g (02 mol) of 2_(thiol)benzonitrile obtained in Production Example 1. 50.0g - gas benzene and 0_7g (〇.〇4mol) water, while stirring on 12 201247637 45~50t; blowing 2 times · 22 moles in 2 hours), while leaving 3 to 2 moles of water (4) Diving in 2 hours. After the end of the blowing of the blown air and the water, the mixture was heated at 65 to 70 ° C for 1 hour. After completion of the reaction, 41 〇g of a 2% by weight aqueous solution of hydrogen hydroxide was added at the same temperature and cooled to room temperature. The precipitated crystals were separated by filtration using a monostyrene benzene and dried to give 29.9 g (0.18 moles of benzoisothiazolone). The yield of 2-(methylthio)benzonitrile was homogeneous. The purity of the obtained α-benzoisothiazol-3-one was 99.8% as measured by high-speed liquid chromatography. Example 2 The internal volume of a blender, a thermometer, a dropping funnel, and a cooling tube was 500 mL. A four-necked flask was charged with 27 5g (〇2mol) 2_gas benzoquinone, 30g-gas benzene and lg 50% by weight of tetra-n-butylammonium bromide aqueous solution under nitrogen atmosphere. 5 μ.4 g (〇.22 mol) of a sodium salt aqueous solution of ruthenium thiol was added dropwise over 5 hours, and after completion of the dropwise addition, the reaction was further carried out at the same temperature for 12 hours. By this operation, 2_( After the reaction is completed, the reaction liquid is cooled to room temperature, and liquid is separated to obtain an organic layer. After the obtained organic layer is added 〇7 g (〇〇4 mol) of water and stirred. 15.6 g (0.22 mol) of gas was blown at 45 to 5 ° C for 2 hours while 3.6 g (0.2 mol) of water was dropped in the same manner for 2 hours. After the completion of the dropwise addition, the reaction was further carried out at 65 to 70. (: Heating was carried out for 1 hour. After the completion of the reaction, 41% by weight of a 2% by weight aqueous sodium hydroxide solution was added and cooled to room temperature. The precipitated crystals were separated by filtration, washed with monostyrene and dried to give 29.9 g (0.198 mol) of 1,2- benzoisothiazole 13 201247637 -3- ketone. Yield relative to 2- benzoquinone The purity of I obtained by 99Q/(^, benzoisothiazol-3-one, as determined by high-speed liquid chromatography, was 99.8%. 'Example 3 In Example 1, except that 35.4 g was used. The same procedure as in Example 1 was carried out except that 2_methyl-2_(ethylthio)benzonitrile was used in the same manner as in Example 1 except that 29.8 g (0-2 mol) of 2-(decylthio)benzonitrile was used. 31 7 g (0 192 mol) of a 7-methylbenzisothiazol-3-one compound was obtained in a yield of 96% relative to a 3-methyl(ethylthio)cyanhydrin compound. The purity of _methyl_丨, 2_ stupid isothiazolone was 99.6% as measured by high-speed liquid chromatography. Example 4 The internal volume of a mixer, thermometer and cooling tube was 5 〇〇m. L Mouth flask, adding 41. 〇g (〇.2 mol) of 5-t-butyl-2-(methylthio)benzoic acid nitrile, 50, 〇g gas benzene and 〇7g (〇〇4 mol) water 29.7g (〇.22mol) sulfur helium gas and 3.6g (0.2mol) water were simultaneously dropped in 2 hours at 45~5〇C while stirring. After the end of the instillation, and then at 65~7 The mixture was heated and allowed to react for 1 hour. After the completion of the reaction, 41.% by weight of a 20% by weight aqueous sodium hydroxide solution was added and cooled to room temperature. The precipitated crystals were separated by filtration, washed with chlorobenzene and dried to give 4 〇.2 g (〇.194 mol) of 5-t-butyl-1,2-benzisothiazol-3-one. The yield based on 5-t-butyl-2-(methylthio)benzonitrile was 97%. The purity of the obtained 5-t-butyl-indole, 2-benzisothiazole-3-ketone was measured by high-speed liquid chromatography and found to be 99 5 Å/〇. Example 5 201247637 In a four-necked flask equipped with a mixer, a thermometer, and a cooling tube, the volume of 5 〇〇m [4, 4, 2, 4, 2, 4 5〇.g g-chlorobenzene and l.lg (water 0.04 mol) of 35 wt% hydrochloric acid, side-mixed; 45 50 C, 15.6 g (〇.22 mol) of chlorine was blown in for 2 hours At the same time, 5.5 g (3.5 ml of hydrochloric acid) of hydrochloric acid was added dropwise in the same manner for 2 hours. After the gas is blown in and the water drops, the thief heats up the money and reacts for 1 hour. After completion of the reaction, 4 丨 0 g of a 20% by weight aqueous sodium hydroxide solution was added at the same temperature and cooled to room temperature. The precipitated crystal transitions were separated, washed with monochlorobenzene and dried to obtain 36.0 g (0194 mol) of gas-丨^-benzo sing. Sit -3-嗣. The yield based on 4-chloro-2-(methylthio)benzonitrile was 97%. The purity of the obtained 6·gas-1,2-benzisoindole _3__ was 99.70/〇 as measured by a high-speed liquid chromatography method. Comparative Example 1 A four-necked flask equipped with a stirrer, a thermometer, and a cooling tube of 5 μm [29.8 g (0.2 mol) of 2-(methylthio)benzonitrile, 5 〇〇g ~ Gas benzene and 4.3 g (0.24 mol) of water were stirred at 45 to 5 Torr with I5.6 g (0-22 mol) gas for 2 hours, and then heated at 65 to 150 ° for 1 hour. After completion of the reaction, 4 μg of a 2% by weight aqueous sodium hydroxide solution was added at the same temperature and cooled to room temperature. The precipitated crystals were separated by filtration, washed with monostyrene and dried to give 29.0 g (0.192 mol) of 1,2-p-isoisothiazol-3-one. The yield based on 2-(decylthio)benzonitrile was 96%. The purity of the obtained Xiayi stupid isothiazol-3-one was determined by high-speed liquid chromatography, which was 97.1%. Simple description of C pattern 3 (none) [Explanation of main component symbols] (none) 16